To improve the lightweight level of electric cargo vehicles, a Cell To Frame (CTF) structure that integrates the frame and battery compartment is proposed in this paper. Firstly, a finite element model of the benchmark vehicle frame is established, and its static performance and free mode are calculated. The accuracy of the finite element model is verified through free mode experiments. Then, the fatigue life analysis of the frame is carried out using the nominal stress method in the time domain using the multi working condition combination fatigue load spectrum obtained from road sampling. Next, experimental design is conducted on the initial design of the CTF structure, which has been validated by finite element analysis, and a surrogate model is established. Finally, the global response search method is used for optimization design to obtain the optimal lightweight solution. The results show that after optimized design, the weight of the CTF structure is reduced by 139.95 kg compared to the traditional separation design of the frame and battery compartment, with a lightweight rate of 14.09%. At the same time, the mechanical properties and fatigue life of the CTF structure both meet the design requirements.